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Accelerated complications in Type 2 diabetes mellitus the need for greater awareness and earlier detection

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ORIGINAL ARTICLES
Accelerated Complications in Type 2
Diabetes Mellitus: The Need for
Greater Awareness and Earlier
Detection
Michele Muggeo*
Division of Endocrinology and Metabolic Diseases
University of Verona, Italy
Persistent hyperglycaemia is the underlying pathogenic factor responsible for chronic
diabetic complications in Type 1 and Type 2 diabetes mellitus. In Type 1 diabetes,
diagnosis is made soon after the onset of hyperglycaemia and several years are required
for the resultant complications to appear clinically. The onset of Type 2 diabetes is
insidious and is usually recognized only 5–12 years after hyperglycaemia develops. During
this period of undiagnosed diabetes, hyperglycaemia, in combination with lifestyle factors
(physical inactivity, alcohol use, smoking), and other metabolic (dyslipidaemia, obesity,
insulin resistance) and haemodynamic (hypertension) abnormalities frequently associated
with Type 2 diabetes, promote the initiation and progression of micro- and macrovascular
complications. Furthermore, when blood glucose levels are increased only slightly and no
symptoms are apparent, the physician may be reluctant to diagnose Type 2 diabetes or
start treatment. This delay in diagnosing the disease results in a high prevalence of chronic
complications at the time of actual diagnosis. Indeed, when Type 2 diabetes is diagnosed,
cardiovascular disease and neuropathy are found in approximately 10% of cases, and
retinopathy and nephropathy in 15–20%. All healthcare providers should be aware of
this phenomenon, which may be termed ‘accelerated complications’, and should plan
thorough screening programmes for these conditions at diagnosis. All reversible risk factors
associated with diabetes should be identified and treated. When acute metabolic
derangements and infections are not the main causes of morbidity and mortality in
diabetes, the costs of diabetes care are related mainly to chronic complications of the
disease. Therefore, because of the high frequency of Type 2 diabetes, the most efficient
method of reducing costs is to increase awareness and secure earlier detection that leads
to fast and aggressive treatment of the accelerated chronic complications often seen in
Type 2 diabetes.  1998 John Wiley & Sons, Ltd.
Diabet. Med. 15 (Suppl. 4): S60–S62 (1998)
KEY WORDS
Type 2 diabetes mellitus; late diabetic complications; cardiovascular
diseases; microvascular complications
Received 3 September 1998; accepted 7 September 1998
Introduction
Persistent hyperglycaemia is the underlying pathogenic
mechanism responsible for chronic diabetic complications in Type 1 and Type 2 diabetes. In Type 1
diabetes, diagnosis is made soon after the onset of
hyperglycaemia and several years are required for the
resultant complications to appear clinically. The onset
of Type 2 diabetes is insidious and is usually recognized
only 5–12 years after hyperglycaemia develops.1 This is
generally a result of the long phase of mild hyperglycaemia in Type 2 diabetes, which is well tolerated by
the patient and is often underestimated by the physician.
Indeed, asymptomatic hyperglycaemia is sometimes con* Correspondence to: M. Muggeo, Divisione di Endocrinologia e
Malattie del Metabolismo, Ospedale Civile Maggiore, 37126 Verona,
Italy
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CCC 0742–3071/98/S40S60–03$17.50
 1998 John Wiley & Sons, Ltd.
sidered only a biochemical abnormality with no substantial clinical implication. This leads to the conclusion that
a thorough screening for chronic complications of
diabetes is unnecessary. However, the two cases
described here contradict this belief and provide evidence
to support more appropriate medical practices.
Case 1
A 46-year-old man was admitted to hospital because of
gangrene of the first and second toe of the left foot. The
patient, a male nurse, had been diagnosed as having
mild hyperglycaemia one year earlier when he consulted
his family physician because of skin lesions with poor
healing on the toes of the left foot. On that occasion
the patient was prescribed gliclazide 80 mg twice daily.
However, the patient showed poor compliance and over
the next months he never consulted his doctor. The
DIABETIC MEDICINE, 1998; 15 (Suppl. 4): S60–S62
ORIGINAL ARTICLES
patient had a positive family history of Type 2 diabetes
and reported low levels of physical activity and cigarette
smoking (15–20 per day) for many years, but had no
previous major health problems. On physical examination, bruits on both sides of the neck were heard; pedal
pulses were not detected; leg muscles were slightly
hypotrophic; leg deep-tendon reflexes were absent;
sensation was reduced on testing with light touch,
pinprick and vibration; body weight was 92 kg; height
was 176 cm; blood pressure was 165/105 mmHg; and
heart rate was 86 beats per minute. On admission,
laboratory tests showed erythrocyte sedimentation rate
(ESR) at 122 mm·h⫺1, fibrinogen 801 mg·dl⫺1 (normal
range 150–450 mg·dl⫺1), haematocrit 47%, white cell
count 10 800 per mm3, neutrophils 78%, glucose 327
mg·dl⫺1 (18.2 mmol·l⫺1), HbA1c 9.2%, cholesterol 242
mg·dl⫺1 (6.3 mmol·l⫺1), triglyceride 312 mg·dl⫺1 (3.5
mmol·l⫺1), high density lipoprotein (HDL) cholesterol 32
mg·dl⫺1 (0.83 mmol·l⫺1) and creatinine 1.4 mg·dl⫺1 (124
␮mol·l⫺1). Urine was positive for protein (1.2 g·day⫺1)
and glucose, and negative for ketones; the sediment
contained three hyaline casts per low-power field and
four red cells per high-power field. Other laboratory
tests were normal. An electrocardiogram showed Q
waves in II, III and aVF leads, which suggests a past
(unrecalled) inferior myocardial infarction. A radiograph
of the left foot showed partial amputation of the distal
phalanx of the first toe and arterial wall calcifications.
Arterial Doppler examination of the legs revealed diffuse
sclerosis and arteriography showed occlusion of the left
superficial femoral artery with partial revascularization
of the popliteal artery by collateral vessels. Sonography
of the carotid arteries revealed carotid plaques on
both sides and a fundus examination showed diabetic
background retinopathy.
Clinical Diagnosis
Type 2 diabetes, diffuse macroangiopathy with ischaemic
gangrene of the first and second toe of the left foot, past
myocardial infarction, nephropathy and background
retinopathy.
Case 2
A 61-year-old woman was admitted to the hospital
because of hyperglycaemia revealed by laboratory workup for urinary symptoms (dysuria, urgency, frequent
urination and suprapubic pain) and a mild increase in
body temperature (37.5–38.0 °C). The patient had always
been well but over the last few years she had periods
of unexplained polyuria, nocturia and polydipsia. She
reported blurred vision over the last few weeks. Family
history of diabetes was negative. The patient had four
babies between the age of 25 and 40, the last two with
a birthweight of 4.3 and 4.8 kg. She reported low levels
of physical activity and excess weight since the first
pregnancy, and smoked 5–10 cigarettes per day between
ACCELERATED COMPLICATIONS IN TYPE 2 DM
 1998 John Wiley & Sons, Ltd.
the age of 17 and 32. Body weight increased substantially
during the last two pregnancies and after the menopause,
but she never followed a diet regularly. On physical
examination, body weight was 85 kg and height was
157 cm, blood pressure was 175/110 mmHg, heart rate
was 102 beats per minute, and a bruit on the right side
of the neck was heard. Laboratory tests showed ESR was
76 mm·h⫺1, fibrinogen 420 mg·dl⫺1, haematocrit 38%,
white cell count 12 000 per mm3, neutrophils 81%,
glucose 264 mg·dl⫺1 (14.7 mmol·l⫺1), HbA1c 10.2%,
cholesterol 288 mg·dl⫺1 (7.4 mmol·l⫺1), triglyceride 286
mg·dl⫺1 (3.2 mmol·l⫺1), HDL cholesterol 36 mg·dl⫺1 (0.9
mmol·l⫺1) and creatinine 1.2 mg·dl⫺1 (106 ␮mol·l⫺1).
Urine was positive for protein (++++) and glucose (++++),
and negative for ketones; the sediment contained red
blood cells, leucocytes and bacteria. Urine culture
showed an infection by Escherichia coli. An electrocardiogram revealed left ventricular hypertrophy and radiographs of the chest showed enlargement of the left
ventricle. Macular oedema in the right eye and bilateral
non-proliferative retinopathy were detected by retinal
examination. An echo-duplex of the carotid arteries
revealed an 80% stenosis of the right internal carotid
artery and several plaques in the common and internal
carotid arteries on both sides.
Clinical Diagnosis
Type 2 diabetes, obesity, urinary tract infection, hypertension, hypertensive heart disease, carotid stenosis and
retinopathy.
Comments
In the first case, ischaemic gangrene of toes led to the
detection of diffuse macroangiopathy (coronary and
carotid arteries) and microangiopathy (nephropathy,
retinopathy and neuropathy). In the second case, the
urinary tract infection revealed diabetes complicated
already by retinopathy, carotid artery stenosis and
hypertensive heart disease. These two cases are typical
examples of a frequent clinical event in which the
diagnosis of Type 2 diabetes is established only when
an intercurrent disease troubles the patient. The presence
of Type 2 diabetes could have been diagnosed long
before the acute episode on the basis of clinical
signs and symptoms, but no medical investigation was
undertaken. The recognition of several associated metabolic disorders and chronic complications of diabetes
was made at the same time as the diagnosis of the disease.
These examples point out that a long period of
hyperglycaemia precedes the diagnosis of Type 2 diabetes
because the elevation of blood glucose is moderate
(140–200 mg·dl⫺1; 7.7–11.0 mmol·l⫺1) and does not
result in signs and symptoms severe enough to draw the
attention of the patient or the physician. Furthermore,
when blood glucose is increased only slightly and no
symptoms trouble the patient, the physician is sometimes
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Diabet. Med. 15 (Suppl. 4): S60–S62 (1998)
ORIGINAL ARTICLES
reluctant to make the diagnosis and begin treatment. In
addition, even before blood glucose reaches levels
diagnostic for diabetes, there is a long period characterized by mild fasting hyperglycaemia (110–140 mg·dl⫺1;
6.1–7.7 mmol·l⫺1) and large postprandial increments of
blood glucose levels.
Mild to moderate hyperglycaemia during the period
of ‘pre-diabetes’ (actual early stages of diabetes) is
sufficient to promote the initiation and progression
of chronic complications. Hyperglycaemia operates in
concert with lifestyle factors (excessive calorie intake,
low level of physical activity, cigarette smoking), and
other metabolic (dyslipidaemia, obesity, insulin
resistance) and haemodynamic (arterial hypertension)
abnormalities, associated frequently with Type 2 diabetes.
With respect to these factors, it is worth noting that
approximately 70% of patients with newly diagnosed
Type 2 diabetes are overweight and as many as 60%
have dyslipidaemia or arterial hypertension.1 These
abnormalities often precede Type 2 diabetes diagnosis
by several years, are frequently untreated and contribute
to the development of atherosclerosis as well as
microangiopathy. The diagnosis of diabetes is therefore
preceded by a long period featured not only by hyperglycaemia but also by a cluster of associated risk factors
that remain totally untreated. As a consequence, in
patients with undiagnosed diabetes, a high prevalence
of chronic complications occurs, e.g. angina pectoris
(approximately 10%), myocardial infarction (approximately 6%), peripheral vascular disease (approximately
10%), carotid stenosis (approximately 10%), peripheral
neuropathy (approximately 10%), nephropathy (approximately 20%) and retinopathy up to 30%.1–4
Interestingly, asymptomatic hyperglycaemia has been
recently shown to be associated with increased mortality.5
Furthermore, other prospective studies have reported that
during follow up the overall mortality (60–70% from
cardiovascular diseases) was even greater in patients
with undiagnosed diabetes at baseline than in known
diabetic individuals.6,7 These data stress the importance
to society and the healthcare system of the burden
of undiagnosed Type 2 diabetes and its ‘accelerated
complications’. All healthcare providers should be aware
of this phenomenon and should look for signs of diabetes
whenever clinically suspected (signs, symptoms, risk
factors), pay the appropriate attention to any abnormality
(even borderline) of blood glucose levels and should
plan a thorough screening of chronic complications from
the time of diagnosis of diabetes. Meanwhile, all reversible
risk factors associated with diabetes should be identified
and treated. Indeed most recently, the United Kingdom
Prospective Diabetes Study (UKPDS) has shown conclusively that intensive treatment of hyperglycaemia8 and
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 1998 John Wiley & Sons, Ltd.
hypertension9 is very effective in reducing the risk of
adverse diabetes-related outcomes.
In times when acute metabolic derangements and
infections are no longer the main causes of morbidity
and mortality in diabetes, the costs society pays for
diabetes care are mainly related to chronic complications
of the disease. As a result of the large preponderance of
Type 2 vs. Type 1 diabetes, the most efficient way to
reduce these costs is to promote increased awareness, and
implement early detection programmes and aggressive
treatment of the accelerated chronic complications of
Type 2 diabetes. The recent proposal from the American
Diabetes Association to reduce the cut-off values for
diabetes diagnosis could favour earlier detection and
initiation of programmes to prevent the accelerated complications.10
References
1.
Harris MI. Undiagnosed NIDDM: clinical and public
health issues. Diabetes Care 1993; 16: 642–652.
2. Aldington SJ, Kohner EM, Nugent A. Retinopathy at entry
in the United Kingdom prospective diabetes study (UKPDS) of maturity onset diabetes. Diabet Med 1987; 4:
355–362.
3. Harris MI, Klein R, Welborn TA, Knuiman MW. Onset of
NIDDM occurs at least 4–7 yr before clinical diagnosis.
Diabetes Care 1992; 15: 815–819.
4. Gall M-A, Rossing P, Skøtt P, Damsbo P, Vaag A, Bech
K, Dejgaard A, Lauritzen M, Lauritzen E, Hougaard P,
Beck-Nielsen H, Parving H-H. Prevalence of micro- and
macroalbuminuria, arterial hypertension, retinopathy, and
large vessel disease in European Type 2 (non-insulindependent) diabetic patients. Diabetologia 1991; 34:
655–661.
5. Lowe PL, Liu K, Greenland P, Metzger BE, Dyer AR,
Stamler J. Diabetes, asymptomatic hyperglycamia, and
22-year mortality in black and white men. Diabetes Care
1997; 20: 163–169.
6. Eschwege E, Richard JL, Thibult N, Ducimetiere P, Warner
JM, Claude Jr, Rosselin GE. Coronary heart disease
mortality in relation with diabetes, blood glucose, and
plasma insulin levels, the Paris Prospective Study ten
years later. Hormone and Metab Res 1985; 15 (Suppl):
41–46.
7. Jarret RJ, Shipley MJ. Type 2 diabetes mellitus and
cardiovascular disease-putative association via common
antecedents; further evidence from the Whitehall Study.
Diabetologia 1988; 31: 737–740.
8. UK Prospective Diabetes Study (UKPDS) Group. Intensive
blood-glucose control with sulphonylureas or insulin
compared with conventional treatment and risk of complications in patients with Type 2 diabetes (UKPDS 33).
Lancet 1998; 352: 837–853.
9. UK Prospective Diabetes Study (UKPDS) Group. Tight
blood pressure control and risk of macrovascular and
microvascular complications in patients with Type 2
diabetes (UKPDS 38). BMJ 1998; 317: 703–713.
10. American Diabetes Association: Report of the Expert
Commitee on the Diagnosis and Classification of Diabetes
Mellitus. Diabetes Care 1997; 20: 1183–1197.
M. MUGGEO
Diabet. Med. 15 (Suppl. 4): S60–S62 (1998)
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